Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212761 | SCV000208917 | pathogenic | not provided | 2022-02-03 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 25691160, 16518851, 19047918, 19966803, 23334668, 28098151, 28594414, 26918529, 29146900) |
Invitae | RCV001066799 | SCV001231819 | pathogenic | RASopathy | 2023-06-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19966803, 21263000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NRAS protein function. ClinVar contains an entry for this variant (Variation ID: 177778). This missense change has been observed in individual(s) with clinical features of a RASopathy (PMID: 28098151, 28594414). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the NRAS protein (p.Gly12Ser). |
Genome Diagnostics Laboratory, |
RCV001813397 | SCV002060956 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2018-11-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001066799 | SCV004029432 | pathogenic | RASopathy | 2023-07-24 | criteria provided, single submitter | clinical testing | Variant summary: NRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). c.34G>A has been reported in the literature in neonates affected with cystic hygroma (example: Mason-Suares_NRAS_EJHG_2017) and an individual affected with Noonan Syndrome reported as a de novo occurrence (example: Altmuller_2017). At-least one study have reported this variant affects the normal activity of the protein (example: Motoda_2007). Other variants affecting the same residue have been classified as pathogenic in ClinVar (examples: CV ID 219097, 40469, 39648, 40470). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genomic Medicine Lab, |
RCV003998247 | SCV004847138 | pathogenic | Noonan syndrome 6 | 2023-09-11 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000158978 | SCV000204071 | pathogenic | Juvenile myelomonocytic leukemia; Noonan syndrome | 2013-12-02 | no assertion criteria provided | clinical testing | The Gly12Ser variant has been identified by our laboratory in one individual wit h juvenile myelomonocytic leukemia (JMML) and dysmorphic features. In addition, this variant has been reported in 3 other individuals with JMML (Yoshida 2009), and was not identified in large population studies. Functional studies have show n the Gly12Ser variant causes constitutive NRAS signaling in the absence of grow th factor (Cirstea 2010). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly12Ser var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other variants at the Gly12 residue in RAS genes (NRAS , KRAS, HRAS) have been associated with multiple cancers, highlighting the impor tance of this position in cell signaling (Schubbert 2007). While this variant ha s not been identified in individuals with classic features of Noonan syndrome, i t is likely due to the severe impact of the variant. In summary, this variant me ets our criteria for pathogenicity for JMML and Noonan-spectrum disorders (http: //pcpgm.partners.org/LMM). |
Database of Curated Mutations |
RCV000430288 | SCV000503746 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439216 | SCV000503747 | pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421993 | SCV000503748 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433097 | SCV000503749 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442594 | SCV000503750 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421327 | SCV000503751 | pathogenic | Non-small cell lung carcinoma | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431995 | SCV000503752 | pathogenic | Melanoma | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445150 | SCV000503753 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427184 | SCV000503754 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only |